2-187498247-C-T

Variant names:

• chr2-187498247-C-T
• rs2041778
• NM_006287.6:c.122-1169G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_006287.6(TFPI):​c.122-1169G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.539 in 151,518 control chromosomes in the GnomAD database, including 23,609 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.54 (23609 hom., cov: 32)
• Consequence: TFPI NM_006287.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.710
• Publications: 4 publications found

Genes affected

TFPI (HGNC:11760): (tissue factor pathway inhibitor) This gene encodes a Kunitz-type serine protease inhibitor that regulates the tissue factor (TF)-dependent pathway of blood coagulation. The coagulation process initiates with the formation of a factor VIIa-TF complex, which proteolytically activates additional proteases (factors IX and X) and ultimately leads to the formation of a fibrin clot. The product of this gene inhibits the activated factor X and VIIa-TF proteases in an autoregulatory loop. Inhibition of the encoded protein restores hemostasis in animal models of hemophilia. This gene encodes multiple protein isoforms that differ in their inhibitory activity, specificity and cellular localization. [provided by RefSeq, Jul 2016]

CALCRL-AS1 (HGNC:55863): (CALCRL and TFPI antisense RNA 1)

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.77 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TFPI	NM_006287.6	c.122-1169G>A		intron_variant	Intron 2 of 7	ENST00000233156.9	NP_006278.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TFPI	ENST00000233156.9	c.122-1169G>A		intron_variant	Intron 2 of 7	1	NM_006287.6	ENSP00000233156.3

Frequencies

GnomAD3 genomes AF: 0.539 AC: 81584 AN: 151402 Hom.: 23615 Cov.: 32

Gnomad AFR AF: 0.311

Gnomad AMI AF: 0.572

Gnomad AMR AF: 0.607

Gnomad ASJ AF: 0.627

Gnomad EAS AF: 0.790

Gnomad SAS AF: 0.582

Gnomad FIN AF: 0.654

Gnomad MID AF: 0.491

Gnomad NFE AF: 0.617

Gnomad OTH AF: 0.542

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.539 AC: 81593 AN: 151518 Hom.: 23609 Cov.: 32 AF XY: 0.543 AC XY: 40180 AN XY: 74038

African (AFR) AF: 0.311 AC: 12868 AN: 41386

American (AMR) AF: 0.607 AC: 9222 AN: 15202

Ashkenazi Jewish (ASJ) AF: 0.627 AC: 2170 AN: 3460

East Asian (EAS) AF: 0.790 AC: 4089 AN: 5176

South Asian (SAS) AF: 0.583 AC: 2808 AN: 4818

European-Finnish (FIN) AF: 0.654 AC: 6893 AN: 10534

Middle Eastern (MID) AF: 0.486 AC: 143 AN: 294

European-Non Finnish (NFE) AF: 0.617 AC: 41749 AN: 67634

Other (OTH) AF: 0.537 AC: 1129 AN: 2102

Alfa AF: 0.564 Hom.: 3116

Bravo AF: 0.530

Asia WGS AF: 0.632 AC: 2170 AN: 3428

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.61
DANN	Benign	0.19
PhyloP100		-0.71
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs2041778; hg19: chr2-188362974;